Our overall aim is to examine the interaction of chemical carcinogens with hemopoietic cells of rodents and primates to better define the target(s) for transformation and the sequence of events which mediate the progression of a chemically induced neoplasm. A number of agents in the environment have been demonstrated to induce cancer in experimental model systems and have been strongly associated with spontaneous neoplasms in humans. During the past decade, methods have been devised which permit a direct analysis of the transformation of a variety of cell types by oncogenic viruses. While the events which accompany virus induction of leukemia and sarcoma can now be readily studied in vitro, many of the strains of transforming viruses have been highly selected for a particular property and may not have general relevance to carcinogenesis by naturally occurring viruses, chemicals or radiation. Furthermore, while the relevance of chemicals and radiation to cancer is clear, very few systems exist wherein one can directly analyze the early and late events in carcinogenesis induced by these agents. At present we have developed a method for recognizing small colonies of hemopoietic stem cells grown in vitro in semisolid cultures. These colonies have tremendous proliferative potential and give rise to secondary colonies which contain the progenitors of white blood cells, red blood cells and platelets. We will culture these stem cells in the presence of a variety of chemicals to test their effect on cellular proliferation, differentiation and hormone sensitivity. In addition, chemically-treated stem cells will be inoculated into irradiated mice which will then be monitored for normal differentiation or hemopoiesis or leukemogenesis. We are hopeful that we will be able to define the target cell an the specific interactions which lead to leukemia.